PHARMACOKINETICS AND PHARMACODYNAMICS

When formulating efficacious dosages there is a require­ment to integrate the pharmacokinetic profile of the drug in the particular species, with its pharmacodynamic action. Pharmacokinetics (PK) is the effect that physio­logical processes have on the drug concentration in the body.

• absorption - the proportion of drug in the circulation compared with that initially administered

• distribution - the proportion of the drug that binds to plasma proteins and the extent to which it can enter body compartments to access its target to induce a response

• metabolism - the chemical conversion of the parent drug into active and/or inactive metabolites

• excretion - the elimination of the parent drug from the body unchanged.

It is the PK processes of absorption, plasma protein binding, differences in body tissue composition, metabo­lism and excretion that may vary significantly between species. The pharmacodynamic mechanism of a xenobi- otic (i.e. the clinical response or medicinal ‘effect’) is usu­ally consistent across species, unless endogenous pharmacokinetic processes are overwhelmed, resulting in the xenobiotic accumulating in body compartments lead­ing to toxicity.

Extrapolation of dosages across species is common (Hunter and Isaza 2008), with the most common approaches being: linear scaling, whereby a single dosage for one species is applied to another; metabolic scaling, where a ratio of a known physiological process or an ana­tomical feature shared between species, is used to esti­mate a dosage; and allometric scaling, where the same PK parameter in many species is plotted versus weight to produce an equation with which to estimate a dosage for another species (Sedgwick 1993). However, these meth­ods may be problematic when extrapolating dosages between domestic species and Australian native mam­mals, as dietary factors (Martinez 2005) and physiologi­cal adaptations (Denny and Dawson 1977) may significantly influence xenobiotic absorption, distribu­tion and elimination.

Prior to 2010 there were few published studies docu­menting the in vivo PK profiles of drugs in Australian mammals. These primarily involved marsupial species such as the common brush-tailed possum (Trichosurus vulpecula) (Eason et al. 1999; Ralston et al. 2001; McDow­ell and McLeod 2007); tammar wallaby (Notamacropus eugenii) (Clark et al. 1982; McLelland et al. 2009) and red-necked wallaby (N. rufogriseus) (Kirkwood et al. 1988). A review by Bolton and Ahokas (1995) discussed what was known about marsupial metabolic pathways and the lack of knowledge on the capacity of marsupials to detoxify agricultural poisons. Since 2010, there have been numerous studies published on therapeutic drugs in the koala (Phascolarctos cinereus) (Griffith et al. 2010; Govendir et al. 2012; Black et al. 2013; Kimble et al. 2013a; Kimble et al. 2013b; Black et al. 2014a; Black et al. 2014b; Kimble et al. 2014; Black et al. 2015; Govendir et al. 2016; Budd et al. 2017; Gharibi et al. 2017, 2019; Govendir 2018; Booth and Nyari 2020; Kimble et al. 2020, 2021; Tokonami et al. 2021; Chen et al. 2022, 2023) demonstrating some significant differences between the PK profiles of the koala and domestic species. Studies in other species since 2010 include clinical trials of the cytotoxins vincristine, doxorubicin and carboplatin for facial tumour disease of Tasmanian devils (Sarcophilus harrisii) (Phalen et al. 2013; Phalen et al. 2015); studies and a review on recommended dosages to treat wombats with sarcoptic mange (Death et al. 2011; Ruykys et al. 2013; Wilkinson et al. 2021; Mounsey et al. 2022; Takano et al. 2023); and enrofloxacin in the eastern ring-tailed possum (Pseudocheirus peregrinus) (Scheelings et al. 2015). The findings of these and other studies are sum­marised in Table 11.1. There have been no pharmacologi­cal studies in monotremes or Australian rodents. Although dosages for domestic rodents may apply to Australian rodent species, for reasons outlined in this chapter, direct extrapolation from domestic species should be considered with caution. There is an extensive international literature on the effects of agricultural pesticides on chiropterans (Best 1973; Clark 1988; O’Shea and Clark 2002; Bayat et al. 2014; Eidels et al. 2016; Takeda et al. 2022), and two pharmacokinetic studies on the antifungal terbinafine and the NSAID meloxicam (Court et al. 2017; Goodnight and Cox 2018). Table 11.2 is a summary of pharmacokinetic studies in some marine mammals that could be useful for formulating dose rates for similar Australian species.

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